A critical feature of the immune system is the ability to distinguish self and non-self. The thymus plays a central role in the development of immune responsiveness. An understanding of the cellular and molecular biology of the thymus would greatly enhance our ability to understand and to treat both immunodeficiencies and autoimmunity. Scurfy is an X-linked lymphoproliferative disease in mice in which we have demonstrated an essential role of the thymus in the disease etiology and expression. The purpose of the proposed studies is to increase our understanding of the scurfy mutant in order to better understand the thymus. We propose the following specific aims. 1. Establish the role of the thymus and thymic cell components in scurfy induction: a) Manipulation of the thymus, to implicate the thymic epithelium in induction o , f scurfy, by using fetal thymic transplants to transfer scurfy to H-2 compatible athymic recipients. b) Manipulation of the thymus, to implicate bone marrow derived antigen presenting cells in the induction of scurfy, using scurfy-SCID mice given normal T cell precursors. 2. Identification of the cells responsible for the mediation and modulation of scurfy. a) Use of adoptive transfers of T cells in athymic H-2 compatible mice. b) Modulation of disease in athymic nude mice given a sf/Y thymic stromal transplant. c) Modulation of disease expression in sf/Y mice which lack B cells.. 3. Determination of the role of H-2 antigens in the induction and expression of scurfy. a) Use of H-2 compatible and H-2 incompatible nude recipients of sf/Y and normal thymuses to determine the role of H-2 in induction and expression of scurfy. b) Use of beta-2 microglobulin deficient mice bred to be scurfy. These mice will have no Class I antigens and will be evaluated in the presence and absence of CD8+ T cells. c) Use of Class II deficient mice bred to be scurfy. Scurfy will be evaluated in these mice in the presence and absence of CD4+ T cells.